This invention relates to a series of amine and amide derivatives, pharmaceutical compositions containing them and intermediates used in their preparation. The compounds of the invention are ligands for the neuropeptide Y Y5 (NPY5) receptor, a receptor which is associated with a number of central nervous system disorders and affective conditions. In addition, many of the compounds of the invention reduce food consumption in a rodent model of feeding.
Regulation and function of the mammalian central nervous system is governed by a series of interdependent receptors, neurons, neurotransmitters, and proteins. The neurons play a vital role in this system, for when externally or internally stimulated, they react by releasing neurotransmitters that bind to specific proteins. Common examples of endogenous small molecule neurotransmitters such as acetylcholine, adrenaline, norepinephrine, dopamine, serotonin, glutamate, and gamma-aminobutyric acid are well known, as are the specific receptors that recognize these compounds as ligands (xe2x80x9cThe Biochemical Basis of Neuropharmacologyxe2x80x9d, Sixth Edition, Cooper, J. R.; Bloom, F. E.; Roth, R. H. Eds., Oxford University Press, New York, N.Y. 1991).
In addition to the endogenous small molecule neurotransmitters, there is increasing evidence that neuropeptides play an integral role in neuronal operations. Neuropeptides are now believed to be co-localized with perhaps more than one-half of the 100 billion neurons of the human central nervous system. In addition to humans, neuropeptides have been discovered in a number of animal species. In some instances the composition of these peptides is remarkably homogenous among species. This finding suggests that the function of neuropeptides is vital and has been impervious to evolutionary changes. Furthermore, neuropeptides, unlike small molecule neurotransmitters, are typically synthesized by the neuronal ribosome. In some cases, the active neuropeptides are produced as part of a larger protein which is enzymatically processed to yield the active substance. Based upon these differences, compared to small molecule neurotransmitters, neuropeptide-based strategies may offer novel therapies for CNS diseases and disorders. Specifically, agents that affect the binding of neuropeptides to their respective receptors or ameliorate responses that are mediated by neuropeptides are potential therapies for diseases associated with neuropeptides.
There are a number of afflictions that are associated with the complex interdependent system of receptors and ligands within the central nervous system; these include neurodegenerative diseases, affective disorders such as anxiety, depression, pain and schizophrenia, and affective conditions that include a metabolic component, namely obesity. Such conditions, disorders and diseases have been treated with small molecules and peptides which modulate neuronal responses to endogenous neurotransmitters.
One example of the class of neuropeptides is neuropeptide Y (NPY). NPY was first isolated from porcine brain (Tatemoto, K. et al. Nature 1982, 296, 659) and was shown to be structurally similar to other members of the pancreatic polypeptide (PP) family such as peptide YY, which is primarily synthesized by endocrine cells in the gut, and pancreatic polypeptide, which is synthesized by the pancreas. Neuropeptide Y is a single peptide protein that consists of thirty-six amino acids containing an amidated C-terminus. Like other members of the pancreatic polypeptide family, NPY has a distinctive conformation that consists of an N-terminal polyproline helical region and an amphiphilic xcex1-helix joined by a characteristic PP-fold (Vladimir, S. et. Al. Biochemistry 1990, 20, 4509). Furthermore, NPY sequences from a number of animal species have been elucidated and all show a high degree of amino acid homology to the human protein ( greater than 94% in rat, dog, rabbit, pig, cow, sheep) (see Larhammar, D. in xe2x80x9cThe Biology of Neuropeptide Y and Related Peptidesxe2x80x9d, Colmers, W. F. and Wahlestedt, C. Eds., Humana Press, Totowa, N.J. 1993).
Endogenous receptor proteins that bind NPY and related peptides as ligands have been identified and distinguished, and several such proteins have been cloned and expressed. Six different receptor subtypes [Y1, Y2, Y3, Y4(PP), Y5, Y6 (formerly designated as a Y5 receptor)] are recognized today based upon binding profile, pharmacology and/or composition if identity is known (Wahlestedt, C. et. al. Ann. NY Acad. Sci. 1990, 611, 7; Larhammar, D. et. al. J. Biol. Chem. 1992, 267, 10935; Wahlestedt, C. et. al. Regul. Pept. 1986, 13, 307; Fuhlendorff, J. U. et. al. Proc. Natl. Acad. Sci. USA 1990, 87, 182; Grundemar, L. et. al. J. Pharmacol. Exp. Ther. 1991, 258, 633; Laburthe, M. et. al. Endocrinology 1986, 118, 1910; Castan, I. et. al. Endocrinology 1992, 131, 1970; Gerald, C. et. al. Nature 1996, 382, 168; Weinberg, D. H. et. al. Journal of Biological Chemistry 1996, 271, 16435; Gehlert, D. et. al. Current Pharmaceutical Design 1995, 1, 295; Lundberg, J. M. et. al. Trends in Pharmaceutical Sciences 1996, 17, 301). Most and perhaps all NPY receptor proteins belong to the family of so-called G-protein coupled receptors (GPCRs). The neuropeptide Y5 receptor, a putative GPCR, is negatively coupled to cellular cyclic adenosine monophosphate (cAMP) levels via the action of adenylate cyclase (Gerald, C. et. al. Nature 1996, 382, 168; Gerald, C. et. al. PCT WO 96/16542). For example, NPY inhibits forskolin-stimulated cAMP production/levels in a neuroblastoma cell line. A Y5 ligand that mimics NPY in this fashion is an agonist whereas one that competitively reverses the NPY inhibition of forskolin-stimulated cAMP production is an antagonist.
Neuropeptide Y itself is the archetypal substrate for the NPY receptors and its binding can elicit a variety of pharmacological and biological effects in vitro and in vivo. When administered to the brain of live animals (intracerebroventricularly (icv) or into the amygdala), NPY produces anxiolytic effects in established animal models of anxiety such as the elevated plus-maze, Vogel punished drinking and Geller-Seifter""s bar-pressing conflict paradigms (Heilig, M. et. al. Psychopharmacology 1989, 98, 524; Heilig, M. et. al. Reg. Peptides 1992, 41, 61; Heilig, M. et. al. Neuropsycho-pharmacology 1993, 8, 357). Thus compounds that mimic NPY are postulated to be useful for the treatment of anxiolytic disorders.
The immunoreactivity of neuropeptide Y is notably decreased in the cerebrospinal fluid of patients with major depression and those of suicide victims (Widdowson, P. S. et. al. Journal of Neurochemistry 1992, 59, 73), and rats treated with tricyclic antidepressants display significant increases of NPY relative to a control group (Heilig, M. et. al. European Journal of Pharmacology 1988, 147, 465). These findings suggest that an inadequate NPY response may play a role in some depressive illnesses, and that compounds that regulate the NPY-ergic system may be useful for the treatment of depression.
Neurdpeptide Y improves memory and performance scores in animal models of learning (Flood, J. F. et. al. Brain Research 1987, 421, 280) and therefore may serve as a cognition enhancer for the treatment of neurodegenerative diseases such as Alzheimer""s Disease (AD) as well as AIDS-related and senile dementia.
Elevated plasma levels of NPY are present in animals and humans experiencing episodes of high sympathetic nerve activity such as surgery, newborn delivery and hemorrhage (Morris, M. J. et. al. Journal of Autonomic Nervous System 1986, 17, 143). Thus chemical substances that alter the NPY-ergic system may be useful for alleviating migraine, pain and the condition of stress.
Neuropeptide Y also mediates endocrine functions such as the release of luteinizing hormone (LH) in rodents (Kalra, S. P. et. al. Frontiers in Neuroendrocrinology 1992, 13, 1). Since LH is vital for mammalian ovulation, a compound that mimics the action of NPY could be useful for the treatment of infertility, particularly in women with so-called luteal phase defects.
Neuropeptide Y is a powerful stimulant of food intake; as little as one-billionth of a gram, when injected directly into the CNS, causes satiated rats to overeat (Clark, J. T. et. al. Endocrinology 1984, 115, 427; Levine, A. S. et. al. Peptides 1984, 5, 1025; Stanley, B. G. et. al. Life Sci. 1984, 35, 2635; Stanley, B. G. et. al. Proc. Nat. Acad. Sci. USA 1985, 82, 3940). Thus NPY is orexigenic in rodents but not anxiogenic when given intracerebroventricularly and so antagonism of neuropeptide receptors may be useful for the treatment of diabetes and eating disorders such as obesity, anorexia nervosa and bulimia nervosa.
In recent years, a variety of potent, structurally distinct small molecule Y1 antagonists has been discovered and developed (Hipskind, P. A. et. al. Annu. Rep. Med. Chem. 1996, 31, 1-10; Rudolf, K. et. al. Eur. J. Pharmacol. 1994, 271, R11; Serradeil-Le Gal, C. et. al. FEBS Lett. 1995, 362, 192; Wright, J. et. al. Bioorg. Med. Chem. Lett. 1996, 6, 1809; Poindexter, G. S. et. al. U.S. Pat. No. 5,668,151; Peterson, J. M. et. al. WO9614307 (1996)). However, despite claims of activity in rodent models of feeding, it is unclear if inhibition of a feeding response can be attributed to antagonism of the Y1 receptor.
Several landmark studies strongly suggest that an xe2x80x9catypical Y1xe2x80x9d receptor and/or the Y5 receptor, rather than the classic Y1 receptor, is responsible for invoking NPY-stimulated food consumption in animals. It has been shown that the NPY fragment NPY2-36 is a potent inducer of feeding despite poor binding at the classic Y1 receptor (Stanley, B. G. et. al. Peptides 1992, 13, 581). Conversely, a potent and selective Y1 agonist has been reported to be inactive at stimulating feeding in animals (Kirby, D. A. et. al. J. Med. Chem. 1995, 38, 4579). More pertinent to the invention described herein, [D-Trp32]NPY, a selective Y5 receptor activator has been reported to stimulate food intake when injected into the hypothalamus of rats (Gerald, C. et. al. Nature 1996, 382, 168). Since [D-Trp32]NPY appears to be a full agonist of the Y5 receptor with no appreciable Y1 activity, the Y5 receptor is hypothesized to be responsible for the feeding response. Accordingly compounds that antagonize the Y5 receptor should be effective in inhibiting food intake, particularly that stimulated by NPY.
A variety of structurally diverse compounds that antagonize the Y5 receptor have been described in various publications. In PCT WO 97/19682, aryl sulfonamides and sulfamides derived from arylalkylamines are described as Y5 antagonists and are reported to reduce food consumption in animals. In PCT WO 97/20820, PCT WO 97/20822 and PCT WO 97/20823, sulfonamides containing heterocyclic systems such as quinazolin-2,4-diazirines, are likewise claimed as Y5 antagonists and reported to reduce feeding. In PCT WO 99/10330, a series of heterocyclic ketones is claimed to be NPY Y5 antagonists. In PCT WO 99/01128, certain diarylimidazole derivatives are claimed as a new class of NPY specific ligands. In PCT WO 98/35944, a series of xcex1-alkoxy and xcex1-thioalkoxyamides are claimed to be NPY Y5 receptor antagonists. In PCT WO 98/35957, a series of amide derivatives are claimed as selective neuropeptide Y receptor antagonists; however, these compounds are structurally different from the compounds of this invention. The amides and amines of this invention that are described herein are novel molecular entities that may have binding motifs that are different from these and other Y5 ligands that have been disclosed in patent applications or publications.
The present invention is related to compounds of formula A 
R1 is independently selected from the group consisting of hydrogen; hydroxy; halo; C1-8alkyl; substituted C1-8 alkyl wherein the substituent is selected from halo, such as chloro, bromo, fluoro and iodo; C1-8alkoxy; substituted C1-8 alkoxy wherein the substituent is selected from halo, such as chloro, bromo, fluoro and iodo; trifluoroalkyl; C1-8 alkylthio and substituted C1-8alkylthio wherein the substituent is selected from halo, such as chloro, bromo, fluoro and iodo, trifluoroC1-8alkyl and C1-8alkoxy; C3-6cycloalkyl; C3-8cycloalkoxy; nitro; amino; C1-6alkylamino; C1-8dialkylamino; C4-8cycloalkylamino; cyano; carboxy; C1-5alkoxycarbonyl; C1-5alkylcarbonyloxy; formyl; carbamoyl; phenyl and substituted phenyl wherein the substituent is selected from halo, hydroxyl, nitro, amino and cyano;
n is 1-2
B1 is hydrogen;
B2 is hydrogen;
xe2x80x83or B1 and B2 may be methylene and joined together form a five or six-membered ring;
m 0-3
R2 is independently selected from the group consisting of hydrogen; hydroxy; C1-6alkyl; C2-6alkenyl; halo, such as fluoro and chloro; C3-7cycloalkyl; phenyl; substituted phenyl wherein the substituent is selected from halo, C1-6alkyl, C1-6alkoxy, trifluoroC1-6alkyl, cyano, nitro, amino, C1-6alkylamino, and C1-6dialkylamino; naphthyl; substituted naphthyl wherein the substituent is selected from halo, C1-6alkyl, C1-6alkoxy, trifluoroC1-6alkyl, cyano, nitro, amino, C1-6alkylamino, and C1-6dialkylamino; phenoxy; substituted phenoxy wherein the substituent is selected from halo, C1-6alkyl, C1-6alkoxy, trifluoroC1-6alkyl, cyano and nitro; a heteroaryl group such as pyridyl, pyrimidyl, furyl, thienyl, and imidazolyl; substituted heteroaryl wherein the substitutent is selected from C1-6alkyl and halo; and heterocycloalkyl such as pyrrolidino or piperidino;
Y is methylene (xe2x80x94CH2xe2x80x94) or carbonyl (Cxe2x95x90O)
L is selected from the group consisting of
C1-8alkylene; C2-10alkenylene; C2-10alkynylene; C3-7cycloalkylene; C3-7cycloalkylC1-4alkylene;
arylC1-4alkylene;
xcex1-aminoC4-7alkylene; 
(N-methylene)piperidin-4-yl; 
(N-methylene)piperidin-4-yl; 
(N-methylene)pyrrolidin-3-yl; 
(N-methylene)-4-acetyl-piperidin-4-yl; 
and (N-methylene)piperidin-4,4-diyl; 
Z is selected from the group consisting of:
aryl; 
N-sulfonamido; 
N-(aryl)sulfonamido; 
arylamido; 
arylureido; 
arylacetamido: 
(aryloxy)carbonylamino; 
2,3-dihydro-2-oxo-1 H-benzimidazol-1-yl; 
and 1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl; 
The aryl group in each case may be substituted as shown.
R3 is independently selected from the group consisting of C1alkyl; substituted Clalkyl wherein the substituent is selected from C,alkoxy and halo; cycloalkyl; substituted cycloalkyl wherein the substituent is selected from Clalkoxy and halo; naphthyl; substituted naphthyl wherein the substituent is selected from halo, nitro, amino and cyano; heteroaryl wherein the heteroaryl group is selected from pyridyl, pyrimidyl, furyl, thienyl and imidazolyl; and substituted heteroaryl wherein the substituent is selected from halo, nitro, amino and cyano;
R4 is independently selected from the group consisting of hydrogen; C1-8alkyl; substituted C1-8alkyl wherein the substituent is selected from alkoxy and halo; hydroxy; halogen; cyano; nitro; amino; C1-8alkylamino and C1-8dialkylamino; C1-8alkoxy; substituted C1-8alkoxy wherein the substituent is halo; hydroxy; halogen; cyano, nitro; amino and C1-8alkylamino and C1-8dialkylamino;
R5 is independently selected from the group consisting of hydrogen; C1-8alkyl; C1-8alkylcarbonyl; aroyl; carbamoyl; amidino; (C1-8alkylamino)carbonyl; (arylamino)carbonyl and arylC1-8alkylcarbonyl;
R6 is independently selected from the group consisting of hydrogen and C1-8alkyl;
p is 1-3;
q is 1-3;
xe2x80x83and enantiomers, diastereomers, and pharmaceutically acceptable salts thereof,
xe2x80x83provided that:
when L is C1-8alkylene, C2-10alkenylene, C2-10alkynylene, C3-7cycloalkylene, C3-7cycloalkylC1-4alkylene, arylC1-4alkylene or xcex1-aminoalkylene;
then Z is phenyl, N-sulfonamido or N-(aryl)sulfonamido;
when L is (N-methylene)piperazin4-yl;
then Z is phenyl or naphthyl;
when L is (N-methylene)pyrrolidin-3-yl or (N-methylene)piperidin-4-yl;
then Z is N-sulfonamido, N-(aryl)sulfonamido, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl; benzamido, phenylureido, phenylacetamido or (phenoxy)carbonylamino;
when L is (N-methylene)4-acetyl-piperidin4-yl;
then Z is phenyl or naphthyl and Y is carbonyl;
when L is (N-methylene)piperidin-4,4-diyl;
then Z is 1-aryl-2,3-dihydro4-oxo-imidazol-5,5-diyl and Y is carbonyl;
and when B1 and B2 are both methylene thus forming a six-membered ring (an aminotetralin) and when L is selected from the group consisting of C1-8alkylene; C2-10alkenylene; C2-10alkynylene or arylC1-4alkylene;
then Z cannot be N-sulfonamido, N-(aryl)sulfonamido or phenyl;
xe2x80x83all enantiomers and diastereomers of compounds of formula A are part of the present invention, as are pharmaceutically acceptable salts thereof.
Preferred compounds among the compounds of this invention are those wherein B1 and B2 form a six-membered ring and m=1-3.
As used herein unless otherwise noted the terms xe2x80x9calkylxe2x80x9d and xe2x80x9calkoxyxe2x80x9d whether used alone or as part of a substituent group, include straight and branched chains having 1-8 carbon atoms. For example, alkyl radicals include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-methyl-3-butyl, 1-methylbutyl, 2-methylbutyl, neopentyl, hexyl, 1-methylpentyl, 3-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. The term xe2x80x9carylxe2x80x9d is intended to include phenyl and naphthyl and aroyl is intended to include arylacyl. The term xe2x80x9cacylxe2x80x9d is intended to include C1-8alkylcarbonyl. The term xe2x80x9chaloxe2x80x9d, unless otherwise indicated, includes bromo, chloro, fluoro and iodo. The term xe2x80x9ccycloalkylxe2x80x9d is intended to include cycloalkyl groups having 3-7 carbon atoms. With reference to substituents, the term xe2x80x9cindependentlyxe2x80x9d means that when more than one of such substituent is possible, such substituents may be the same or different from each other.
Those compounds of the present invention which contain a basic moiety can be converted to the corresponding acid addition salts by techniques known to those skilled in the art. Suitable acids which can be employed for this purpose include hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, cinnamic, mandelic, methanesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, or saccharin, and the like. In general, the acid addition salts can be prepared by reacting the free base of compounds of formula A with the acid and isolating the salt.
Pharmaceutical compositions containing one or more of the compounds of the invention described herein as the active ingredient can be prepared by intimately mixing the compound or compounds with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral). Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like; for solid oral preparations, such as powders, capsules and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate the major site of absorption. For parenteral administration, the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation. Injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
For the treatment of disorders of the central nervous system, the pharmaceutical compositions described herein will typically contain from 1 to about 1000 mg of the active ingredient per dosage; one or more doses per day may be administered. Determination of optimum doses and frequency of dosing for a particular disease state or disorder is within the experimental capabilities of those knowledgeable in the treatment of central nervous system disorders. The preferred dose range is 1-100 mg/kg.
As modulators of the NPY5 receptor, the compounds of Formula A are useful for treating feeding disorders such as obesity, anorexia nervosa and bulimia nervosa, and abnormal conditions such as epilepsy, depression, anxiety and sexual/reproductive disorders in which modulation of the NPY5 receptor may be useful. The compounds compete with the endogenous ligands NPY and PYY and possibly non-endogenous ligands, and bind to the NPY5 receptor. In addition, the compounds demonstrate antagonist activity by antagonizing the action of NPY upon binding to the Y5 receptor.
The compounds described herein are ligands of the NPY5 receptor, but are not necessarily limited solely in their pharmacological or biological action due to binding to this or any neuropeptide, neurotransmitter or G-protein coupled receptor. For example, the described compounds may also undergo binding to dopamine or serotonin receptors. The compounds described herein are potentially useful in the regulation of metabolic and endocrine functions, particularly those associated with feeding, and as such, may be useful for the treatment of obesity. In addition, the compounds described herein are potentially useful for modulating other endocrine functions, particularly those controlled by the pituitary and hypothalamic glands, and therefore may be useful for the treatment of inovulation/infertility due to insufficient release of luteinizing hormone (LH) or luteal phase defect.
The present invention comprises pharmaceutical compositions containing one or more of the compounds of Formula A. In addition, the present invention comprises intermediates used in the manufacture of compounds of Formula A.
Examples of particularly preferred compounds of formula A include: 
The amines and amides of formula A that comprise this invention are synthesized via several distinct chemical syntheses as outlined in Schemes 1-26; each synthetic route consists of several sequential chemical operations that can be generalized as described below. In cases in which B1 and B2 together form a six-membered ring or a five-membered ring (an aminotetralin or an aminoindane, respectively), the general synthesis entails the following operations:
Introduction of the xcex1-substituent onto the tetralone (or indanone) nucleus
Conversion to the corresponding xcex1-substituted-xcex2-aminotetralin (or xcex1-substituted-aminoindane)
Acylation of the aminotetralin (or aminoindane) to afford amides of formula A
Reduction to produce amines of formula A
Protecting group manipulations may be needed at various stages of the syntheses.
In cases where B1 and B2 are hydrogen, the general synthesis consists of the following operations:
Introduction of the xcex1-substituent onto a phenylacetonitrile
Reduction to the corresponding xcex2substituted phenethylamine
Acylation of the phenethylamine to afford amides of formula A
Reduction to produce amines of formula A
Protecting group manipulations may be needed at various stages of the syntheses.
It is generally preferred that the respective product of each process step be separated from other components of the reaction mixture and subjected to purification before its use as a starting material in a subsequent step. Separation techniques typically include evaporation, extraction, precipitation and filtration. Purification techniques typically include column chromatography (Still, W. C. et. al., J. Org. Chem. 1978, 43, 2921), thin-layer chromatography, crystallization and distillation. The structures of the final products, intermediates and starting materials are confirmed by spectroscopic, spectrometric and analytical methods including nuclear magnetic resonance (NMR), mass spectrometry (MS) and liquid chromatography (HPLC). In the descriptions for the preparation of compounds of this invention, ethyl ether, tetrahydrofuran and dioxane are common examples of an ethereal solvent; benzene, toluene, hexanes and cyclohexane are typical hydrocarbon solvents and dichloromethane and dichloroethane are representative halohydrocarbon solvents. In those cases wherein the product is isolated as the acid addition salt the free base may be obtained by techniques known to those skilled in the art. In those cases in which the product is isolated as an acid addition salt, the salt may contain one or more equivalents of the acid.
Specifically, an appropriately substituted xcex2-tetralone (II) is reacted with an aryl or heteroaryl aldehyde in the presence of a base such as piperidine, in an inert halohydrocarbon, ethereal or hydrocarbon solvent, such as benzene, from ambient temperature to reflux, to afford the corresponding xcex1-benzylidenyl-xcex2-tetralone or xcex1-heteroarylmethylidenyl-xcex2-tetralone (III). The xcex2-tetralone (III) is dissolved in an inert hydrocarbon, ethereal, ester or alcohol solvent, such as methanol, and reacted with hydrogen gas at a pressure from ambient pressure to 100 p.s.i. in the presence of a suitable catalyst such as palladium on carbon. The reaction is performed at a temperature from ambient temperature to reflux, to yield the desired xcex1-substituted-xcex2-tetralone (IV) (Scheme 1).
An alternative method for the preparation of xcex1-substituted-xcex2-tetralones (IV) involves the reaction of an appropriately substituted xcex2-tetralone (II) with a base such as pyrrolidine in an inert halohydrocarbon solvent such as dichloromethane or hydrocarbon solvent such as benzene, under Dean-Stark conditions (removal of water) or in an alcohol solvent such as methanol, from ambient temperature to reflux, to afford enamine (V). Alkylation of enamine (V) is accomplished by reaction with a benzylic, heterocyclicalkyl or an allylic halide in an inert solvent such as acetonitrile, at a temperature from ambient temperature to reflux, to afford the xcex1-substituted-xcex2-iminium salt (VI). Hydrolysis of the salt (VI) to produce the desired xcex1-substituted-xcex2-tetralone product (IV) is accomplished by reaction of (VI) with water and an inorganic or organic acid such as hydrochloric or glacial acetic acid in an inert hydrocarbon, ethereal, alcohol or halohydrocarbon solvent, or a mixture thereof, such as methanol and dichloromethane (Scheme 1). 
The xcex1-substituted-xcex2-tetralones (IV) are converted to the corresponding aminotetralins via reaction with an ammonium salt such as ammonium acetate in the presence of a reducing agent such as sodium cyanoborohydride, for example, in an inert halohydrocarbon, hydrocarbon, ethereal or alcohol solvent such as methanol to produce the cis-aminotetralin (VII). In some cases, the trans-aminotetralin (VIII) is also formed as a minor product; both sets of diastereomers are part of this invention. The aminotetralins (VII) can also be isolated as acid addition salts by treatment with an organic or an inorganic acid, such as trifluoroacetic acid or hydrochloric acid, for example (Scheme 2). 
Compounds in which m=0 are prepared from an appropriately substituted aminotetralin (VII; m=0) starting from 1-tetralones using the synthetic sequence shown in Scheme 2a. 
Substituted phenethylamines (XI) are prepared by reacting an appropriately substituted phenylacetonitrile (IX) with an aryl or heteroaryl aldehyde in the presence of a base, such as sodium methoxide, in an inert alcohol solvent, such as methanol, at a temperature from ambient temperature to reflux, to afford xcex1,xcex2-unsaturated nitrile (X). Subsequent reduction of nitrile (X), for example, via reaction with hydrogen gas in the presence of a platinum oxide catalyst at a pressure from atmospheric pressure to approximately 100 psi, in an inert solvent such as aqueous alcohol, at a temperature from ambient temperature to reflux, affords xcex2-substituted phenethylamine (XI). Alternatively, reaction of phenylacetonitrile (X) with an arylalkyl-, heteroarylalkyl- or alkyl halide, for example, such as allyl bromide in the presence of a base such as sodium methoxide or sodium hydride, in an inert solvent such as tetrahydrofuran or acetonitrile respectively, at a temperature from ambient to reflux, affords xcex1-substituted phenylacetonitrile (XII). Subsequent reduction of nitrile (XII), for example, by hydrogenolysis, produces xcex2-substituted phenethylamine (XI) (Scheme 3). 
The xcex2-aminotetralins (VII) and the phenethylamines (XI) described above are acylated via suitable amidation methods (see Gross and Meienhofer, Eds., xe2x80x9cThe Peptidesxe2x80x9d, Vols. 1-3, Academic Press, New York, N.Y., 1979-1981). A carboxylic acid is converted to an activated ester via peptide coupling methods known to those skilled in the art, and subsequently reacted with an aminotetralin (VII) or phenethylamine (XI), to afford the corresponding amides.
For example, a carboxylic acid such as trans-4-(2-fluorobenzenesulfonamido)methylcyclohexane carboxylic acid or 4-(tert-butoxycarbonyl)aminomethylcyclohexane carboxylic acid is reacted with HBTU (2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate and an appropriate phenethylamine (XI), in the presence of a base such as diisopropylethylamine, in an inert solvent such as N,N-dimethylformamide, at a temperature from ambient temperature to reflux, to afford amide (XIII) or amide (XIV) respectively. Cleavage of the BOC (butoxycarbonyl) protecting group from carbamate (XIV) with trifluoroacetic acid produces the free amine, which is sulfonylated to yield amide (XIII).
The N-substituted phenethylamine compounds A of the invention are prepared via reduction of amide (XIII) by reaction with a suitable reducing agent such as borane-tetrahydrofuran complex or lithium aluminum hydride in an inert hydrocarbon solvent such as toluene or ethereal solvent such as tetrahydrofuran, at a temperature from ambient temperature to reflux. The final product can be isolated as an acid addition salt upon treatment with a suitable organic acid such as trifluoroacetic acid or an inorganic acid such as hydrochloric acid (Scheme 4). 
Aminotetralin analogs (B1 and B2 each are methylene) are prepared using the chemistry described above but replacing the phenethylamine (XI) starting material with an aminotetralin (VII) (Scheme 5). 
Compounds of formula A in which Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl and L=(N-methylene)piperidin-4-yl are prepared from xcex2-aminotetralins (VII) or phenethylamines (XI) and [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetic acid (Schemes 6-7). For example, 4-(2-keto-1-benzimidazolinyl)piperidine is reacted with a bromoacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [4-(2-keto-1-benzimidazolinyl)piperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [4-(2-keto-1-benzimnidazolinyl)piperidin-1-yl]acetic acid. This carboxylic acid is reacted directly with xcex2-aminotetralins (VII) or phenethylamines (XI), in the presence of an amine base, under peptide coupling conditions described above, to afford benzimidazolinones (XVII) and (XVIII) of formula A in which Y =carbonyl and L=(N-methylene)piperidin-4-yl (Schemes 6-7). 
Compounds of formula A in which Y=methylene and L=(N-methylene)piperidin4-yl and Z=2,3-dihydro-2-oxo-1H-benzimidazol-1-yl are prepared by reduction of amide (XVII) and amide (XVIII) with a reducing agent such as borane-tetrahydrofuran complex or lithium aluminum hydride as described above. The use of an aminotetralin (VII) starting material gives rise to products (XIX) (Scheme 8) whereas phenethylamines give the analogous amines (XX) (Scheme 9). 
Compounds of formula A in which Y=carbonyl, L=(N-methylene)piperazin-4-yl and Z=phenyl are prepared by reacting a phenylpiperazine with a haloacetic acid ester, such as, for example, ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl (4-arylpiperazin-1-yl)acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, (4-arylpiperazin-1-yl)acetic acid. This carboxylic acid is reacted with xcex2-aminotetralins (VII) or phenethylamines (XI), in the presence of a base, such as triethylamine for example, under peptide coupling conditions described above, to afford arylpiperidines (XXI) and (XXII) respectively, of formula A in which Y=carbonyl, L=(N-methylene)piperazin-4-yl and Z=aryl or substituted aryl (Schemes 10-11). 
Compounds of formula A in which Y=methylene, L=(N-methylene)piperazin-4-yl and Z=aryl are prepared by reduction of amides (XXI) and (XXII) with a reducing agent such as borane-tetrahydrofuran complex or lithium aluminum hydride (see Scheme 9) to afford aminotetralins (XXIII) and phenethylamines (XIV) respectively (Schemes 12-13). 
Replacement of 4-arylpiperazines with 4-arylpiperidines in Schemes 10 and 11 affords tetralinamides (XXV) and phenethylamides (XXVI) of formula A in which L=(N-methylene)piperidin-4-yl, Z=aryl and Y=carbonyl (Schemes 14-15). 
Separately, reduction of amides (XXV) and (XXVI) with a reducing agent such a borane-tetrahydrofuran complex, affords amines (XXVII) and (XXVIII) of formula A in which L=(N-methylene)piperidin4-yl, Z=aryl and Y=methylene (Scheme 16). 
Compounds of formula A in which Y=carbonyl, L=(N-methylene)pyrrolidin-3-yl and Z=N-(aryl)sulfonamido are prepared by reacting a suitably protected aminopyrrolidine, such as (3-t-butoxycarbonylamino)pyrrolidine with a haloacetic acid ester, such as, for example, ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [(3-t-butoxycarbonylamino)pyrrolidin-1-yl]acetic acid. This carboxylic acid is reacted with xcex2-aminotetralins (VII) or phenethylamines (XI), in the presence of a base, such as triethylamine for example, under peptide coupling conditions described above, to afford tetralinamides (XXIX) and phenethyamides (XXX) respectively. Subsequent treatment with an organic or inorganic acid, such as trifluoroacetic acid and hydrochloric acid for example, produces the free terminal amines (XXXI) and (XXXII). These materials are sulfonylated by reaction with sulfonyl halides such as benzenesulfonyl chloride for example, in the presence of a base, to afford tetralinamides (XXXIII) and phenethylamides (XXXIV) (Schemes 17-18). 
Separately, reduction of amides (XXXIII) and (XXXIV) With a reducing agent such a borane-tetrahydrofuran complex, affords amines (XXXV) and (XXXVI) of formula A in which L=N-(methylene)pyrrolidin-3-yl and Z=sulfonamido or (aryl)sulfonamido, Y=methylene (Scheme 19). 
Tetralinamides and phenethylamides of formula A in which Y=carbonyl, L=(N-methylene)pyrrolidin-3-yl and Z=benzamido, phenylureido, phenylacetamido and phenoxycarbonylamino (or butoxycarbonylamino) are prepared by reacting amines (XXXI) and (XXXII) respectively, in an inert solvent at a temperature from ambient temperature to reflux, in the presence of a base such as an amine or hydroxide, with an aroyl halide, an arylisocyanate, an arylacetyl halide or a chloroformate such as phenylchloroformate (or di-tert-butyl dicarbonate) to afford benzamides (XXXVII) and (XXXXI), phenylureas (XXXVIII) and (XXXXII), phenylacetamides (XXXIX) and (XXXXIII) and phenylcarbamate (XXXX) and (XXXIV) respectively (Schemes 20-21). 
Compounds of formula A in which Y=methylene, L=N-(methylene)pyrrolidin-3-yl and Z=benzamido, phenylureido, phenylacetamido and phenylcarbonylamino (or butoxycarbonylamino) are prepared by reducing amides (XXXI) and (XXXII) to their respective amines (XXXXV) and (XXXXVI) by treatment with a reducing agent such as borane-tetrahydrofuran complex or lithium aluminum hydride. Amines (XXXXV) and (XXXXVI) are subsequently separately reacted with an aroyl halide, an arylisocyanate, an arylacetyl halide or an arylchloroformate (or carbonate such as di-tert-butyl carbonate), in the presence of a base in an inert solvent as described in Scheme 20-21, to afford benzamides (XXXXVII) and (XXXXXI), phenylureas (XXXXVIII) and (XXXXXII), phenylacetamides (XXXXIX) and (XXXXXIII) and phenylcarbamates (XXXXX) and (XXXXXIV), respectively (Schemes 22-24). 
Substituting an appropriately protected aminopiperidine, such as (4-t-butoxycarbonylamino)piperidine for (3-t-butoxycarbonylamino)pyrrolidine in Schemes 17-24 affords compounds of formula A in which L=(N-methylene)piperidin-4-yl, Y=methylene or carbonyl and Z=N-(aryl)sulfonamido, sulfonamido, benzamido, phenylureido, phenylacetamido or (phenoxy)carbonylamino.
Compounds of formula A in which Y=carbonyl, L=(N-methylene)piperidin-4,4-diyl and Z=1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl are prepared by reacting 1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one with a haloacetic acid ester, such as ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature from ambient temperature to reflux, to afford ethyl (1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an alcoholic solution such as aqueous methanol, to yield upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, (1-aryl-1,3,8-triazaspiro-[4,5]decan-4-one-8-yl)acetic acid. This carboxylic acid is reacted directly with xcex2-tetralins (VII) or phenethylamines (XI), in the presence of a base such as triethylamine for example, under peptide coupling conditions described above, to afford aminotetalinamides (XXXXXV) and phenethylamides (XXXXXVI) respectively, of formula A in which Y=carbonyl, L=(N-methylene)piperidin-4,4-diyl and Z=1-aryl-2,3-dihydro-4-oxo-imidazol-5,5-diyl (Schemes 25-26). 
Compounds of formula A in which L (N-methylene)4-acetyl-piperidin-4-yl and Z=phenyl are prepared by reacting 4-acetyl-4-phenylpiperidine with a haloacetic acid ester, such as, for example, ethyl bromoacetate, in the presence of an amine base, such as diisopropylethylamine, in an inert solvent such as acetonitrile, at a temperature ranging from ambient temperature to reflux, to afford ethyl [(4-acetyl-4-phenylpiperidin-1-yl]acetate. This ester is subjected to hydrolysis under basic conditions, for example, by treatment with sodium hydroxide in an aqueous methanol, to yield, upon acidification with an inorganic or organic acid such as hydrochloric or acetic acid for example, [(4-acetyl-4-phenylpiperidin-1-yl]acetic acid. This carboxylic acid is reacted with xcex2-aminotetralins (Vll) or phenethylamines (XI), in the presence of a base, such as triethylamine for example, under peptide coupling conditions described above, to afford (tetralinamido)arylpiperidines (XXXXXVII) and (phenethylamido)arylpiperidines (XXXXXVIII) respectively, of formula A in which Y=carbonyl, L=(N-methylene)-4-acetyl-piperidin-4-yl and Z=phenyl (Schemes 27-28). 
Other compounds of this invention having the formula A can be prepared using the methods described herein; modifications of the experimental protocols described above are known or obvious or within the ability of those skilled in the art. For example, a variety of xcex2-tetralones are known or readily prepared by reaction of phenylacetic acids with ethylene gas in the presence of a Lewis acid (for example, Stjernlof, P. et. al. J. Med. Chem. 1995, 38, 2202); these compounds can be directly converted to aminotetralins (VII) via reductive amination (Scheme 2). Phenethylamine intermediates (XI) are accessible from phenylacetonitriles using literature methods (Jounral, Hawes and Wibberley, J. Chem. Soc. C. 1966, 315 and 320; also see J. Am. Chem. Soc. 1989, 111, 5954 and Synthesis 1997, 11, 1268) and can be used to prepare compounds of formula A in which B1 and B2 are both hydrogen (Scheme 3). Compounds in which the R1 group(s) is varied can be obtained using the chemistry described above; in some cases, protecting group manipulations are used and these are obvious or known to those skilled in the art. Examples include masking an amine group as a carbamate, amide or phthalamide, and masking an hydroxyl group as an ether or ester. Other R1 substituents are available through functional group manipulations such as, for example, reduction of a nitro group to an amine or dehydration of an amide to a nitrile.
Variation of the R2 group is readily accomplished by using substituted benzaldehydes, naphthylaldehydes and heteroaryl carboxaldehydes, or by using alkyl, alkylenic, alkynylic and benzylic halides, or by using phenoxyalkyl and haloalkyl halides in Schemes 1 and 3. Compounds in which the L group is varied, are derived from piperazines, piperidines or pyrrolidines as described in Schemes 6, 10, 14, 17 and 25. Compounds in which L is alkylene, alkenylene, alkynylene, cycloalkylene or cycloalkylalkylene are derived from amino-carboxylic acids such as aminohexanoic acid, aminohexenoic acid, aminohexynoic acid. Compounds in which L is xcex1-aminoalkylene are derived from amino acids such as lysine which can be used in the racemic or enantiomeric form.
Compounds of formula A where Z is sulfonamido or (aryl)sulfonamido, in which either the R3 or the R4 group is varied, are accessible by sulfonylation; there are hundreds of sulfonyl halides or sulfonic acids that are commercially available and more that are known. Compounds of formula A where Z is sulfonamido or (aryl)sulfonamido, in which the R3 substituent is heteroaryl can be prepared by substituting a pyridinyl, thienyl or furyl sulfonylchloride for a benzenesulfonamide as described in Schemes 4-5. Similarly, alkylsulfonyl and cycloalkylsulfonyl halides, alone or in the presence of an activating agent such as a Lewis acid, can be used to prepare sulfonamides of formula A in which the R3 substituent is alkyl or cycloalkyl respectively. Compounds in which Z is phenyl or aryl are obtained directly from arylpiperazines and arylpiperidines as described in Schemes 10 and 14 respectively; hundreds of arylpiperazines and arylpiperidines are known or commercially available and can be used to make compounds of this invention. Compounds of formula A where Z is benzamido, phenylureido, phenylacetamido, (phenoxy)carbonylamino are prepared from aroyl halides, isocyanates, phenylacetyl halides and chloroformates as described in Schemes 20-21 and 23-24 and hundreds of reagents of these kinds are commercially available or known.
Compounds of formula A in which B1 and B2 are joined together to form a five-membered ring (an aminoindane) are prepared starting from an indanone and using the chemistry described herein. It is preferable to use a symmetrical indan-2-one to avoid the formation of regiochemical isomers which are difficult to separate.